The overall objective of this proposal is to characterize the pathophysiologic role of neutrophil adherence in the setting of cardiopulmonary bypass. Recent experimental evidence suggests that neutrophils may be activated during cardiopulmonary bypass, perhaps due in part, to complement activation. Yet the process and consequences of neutrophil activation are complex, and the data available to date are insufficient to explain the complicated interactions of inflammatory events that may be operative in this setting. While virtually any organ system may suffer tissue damage following cardiopulmonary bypass, clinical experience and experimental data both suggest that the lung may be particularly vulnerable to this injury process. Current evidence links the accumulation of neutrophils in the lungs with the lung tissue damage that sometimes follows cardiopulmonary bypass procedures. It is proposed that this accumulation of neutrophils and their contributions to tissue damage are determined by the interactions of neutrophils with the pulmonary vascular endothelial cells, and that these interactions necessarily involve specific molecular mechanisms of intercellular adhesion. Furthermore, since current research clearly shows that essential receptors and counter-receptors (or ligands) exist on both cell types, there are necessary contributions of both neutrophils and endothelial cells in the pathogenesis of pulmonary damage. Specific Aims of this proposal are: 1) To determine the quantitative and functional changes that occur in the expression of the neutrophil adherence molecules Mac-I (CD II b/CD18), LFA-1 (CDIIa/CD18) and LAM-1, and to correlate their expression with complement activation before, during, and after cardiopulmonary bypass: and to examine the physiologic responsiveness of neutrophils in vitro to a variety of chemotactic stimuli in order to assess their potential in vivo responsiveness. 2) To examine the lung for changes in tissue distribution of endothelial adherence ligands predisposing it to neutrophil-mediated injury, and to determine the nature of pulmonary tissue injury following cardiopulmonary bypass. Studies will include immunohistochemical staining of biopsy specimens before and after bypass for the expression of endothelial adhesion molecules ICAM-1, ELAM-1, and GMP-140 as well as light and electron microscopy examining neutrophil localization and tissue injury. Cannulation of pulmonary lymphatic vessels will allow for studies to assess microvascular permeability changes as well as to examine the lymph for locally produced factors contributing to neutrophil activation and/or induction of endothelial cell adherence ligands. Gravimetric studies to assess extravascular water will be a measure of pulmonary injury. 3) To determine the pathologic significance of neutrophil-endothelial cell adherence to the development of pulmonary injury by utilizing monoclonal antibodies directed at each of the specific adherence determinants outlined in aims I and 2 in an effort to reduce the degree of tissue damage as measured by the parameters previously described.